The nuclear receptor ROR-alpha is a critical myogenic regulator of the cardiomyocyte transcriptome, including the...

We recently found that the nuclear receptor retinoic acid-related orphan nuclear receptor alpha (RORα) protects against angiotensin II-induced cardiac hypertrophy and promotes cardiomyocyte mitophagy. The underlying molecular basis for these salutary effects remains unclear.

We used RNA microarrays to profile the cardiac transcriptomes of "staggerer" (RORα ^sg/sg ) mice that carry a naturally occurring mutation in the ligand-binding domain of RORα, resulting in a global loss-of-function genetic model. We then used genetic and pharmacologic loss-and-gain of function studies in cultured cardiomyocytes to ascertain whether RORα regulates transcription of Adra1a , the gene that encodes the alpha-1A-adrenergic receptor (α1A-AR).

The absence of functional RORα results in broad transcriptional changes in the heart providing a likely molecular basis for the RORα ^sg/sg cardiac phenotype. In vivo and in vitro studies confirmed that RORα directly regulates Adra1a transcription. This effect is enhanced by hypoxia.

Collectively these findings position RORα as a previously unrecognized central regulator of the cardiac myogenic transcriptome and the first recognized transcriptional regulator of Adra1a in cardiomyocytes. Future studies will probe the contribution of RORα-mediated transcriptional regulation of Adra1a to both the response to cardiomyocyte injury and maintenance of circadian biology.